Mercaptosulfide inhibitors and other MMP inhibitors have been identified as potential modulators of the physiological and pathological processes and disease conditions in which matrix metalloproteinases (MMPs) are believed to play significant functions (Sternlicht, M. D., Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001; 17, 463-516; Mercer B. A., Kolesnikova N., Sonett J., D'Armiento J. Extracellular regulated kinase/mitogen activated protein kinase is up-regulated in pulmonary emphysema and mediates matrix metalloproteinase-1 induction by cigarette smoke. J. Biol. Chem. 2004. 279:17690-17696; Pfefferkorn, T., Rosenberg, G. A. Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion. Stroke. 2003; 34, 2025-2530; M. A. Schwartz and H. E. Van Wart, 1995, U.S. Pat. No. 5,455,262, Mercaptosulfide metalloproteinase inhibitors; C. F. Purchase, Jr., B. D. Roth, and A. D. White, 2003, U.S. Pat. No. 6,624,196 B2, Benzene butyric acids and their derivatives as inhibitors of matrix metalloproteinases; Schwartz, M. A., Jin, Y., Hurst, D. R., Sang, Q.-X. Patent Cooperation Treaty (PCT) International Application Pub. No. WO 2005/032541 A1, Substituted Heterocyclic mercaptosulfide Inhibitors; De Crescenzo G., Abbas Z. S., Freskos, J. N., Getman, D. P., Heintz, R. M., Mischke, B. V., McDonald, J. J. 2004, U.S. Pat. No. 6,747,027 B1, Thiol sulfonamide metalloprotease Inhibitors; Levin, J. I., Li, Z., Diamantidis, G., Lovering, F. E., Wang, W., Condon J. S., Lin, Y. I., Skotnicki, J. S., and Park, K., U.S. Patent Application Pub. No. US 2006/0211730 A1, Beta-sulfonamide hydroxamic acid inhibitors of TACE/matrix metalloproteinase; D. R. Hurst, M. A. Schwartz, Y. Jin, M. A. Ghaffari, P. Kozarekar, J. Cao, and Q.-X. Sang. Inhibition of enzyme activity and cell-mediated substrate cleavage of membrane type 1-matrix metalloproteinase by newly developed mercaptosulphide inhibitors. Biochem. J. 2005; 392, 527-536; Sang, Q. X., Jin, Y., Newcomer, R. G., Monroe, S. C., Fang, X., Hurst, D. R., Lee, S., Cao, Q., Schwartz, M. A. Matrix Metalloproteinase Inhibitors as Prospective Agents for the Prevention and Treatment of Cardiovascular and Neoplastic Diseases. Curr. Top. Med. Chem. 2006; 6, 289-316; Hu, J., Van den Steen, P. E., Sang, Q. X., Opdenakker, G. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat. Rev. Drug Discov. 2007; 6, 480-498; M. E. Muroski, M. D. Roycik, R. G. Newcomer, P. E. Van den Steen, G. Opdenakker, H. R. Monroe, Z. J. Sahab, and Q.-X. Sang. Matrix Metalloproteinase-9/Gelatinase B is a Putative Therapeutic Target of Chronic Obstructive Pulmonary Disease and Multiple Sclerosis. Current Pharmaceutical Biotechnology, 2008; 9, 34-46; Kawasaki, Y., Xu, Z. Z., Wang, X., Park, J. Y., Zhuang, Z. Y., Tan, P. H., Gao, Y. J., Roy, K., Corfas, G., Lo, E. H., Ji, R. R. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat. Med. 2008; 14, 331-336). For example, such physiological and pathological processes and disease conditions include the prevention and treatment of (1) cancer invasion, angiogenesis, and metastasis; (2) stroke and chronic cerebral vascular dementia; (3) cardiovascular diseases such as myocardial infarction, atherosclerosis, and restenosis; (4) neuroinflammatory diseases; (5) neurodegenerative diseases such as Alzheimer's; (6) autoimmune diseases; (7) multiple sclerosis; (8) spinal cord injury; (9) arthritic diseases; (10) psoriasis; (11) periodontal disease, as inhibitors may be added to toothpastes and mouthwashes; (12) inflammation disorders; (13) Crohn's disease and irritable bowel syndrome; (14) pain and pain-related pathologies; (15) cartilage and bone diseases; (16) skin/muscular skeletal injuries and disorders; (17) corneal ulceration and other eye diseases (where MMP inhibitors may be used in eye drops or as drugs put into/onto contact lenses); (18) diabetic retinopathy and other complications; (19) adipogenesis and obesity; (20) tissue ulceration; (21) wound healing and regeneration disorders; (22) kidney diseases such as glomerulonephritis; (23) respiratory and lung diseases and disorders such as allergies, asthma, chronic obstructive pulmonary disorders, and emphysema; (24) infection of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS); (25) septic shock syndromes; (26) cachexia and anorexia; (27) organ preservation for transplantation; (28) control of fertility and reproductive capabilities, such as fertilization, implantation, uterine bleeding, birth control, and contraception; (28) blister formation; (29) bone remodeling; (30) osteoporosis; (31) meningitis; (32) malaria; (33) mycobaterial infection; (34) aging and rheumatic disorders; (35) connective tissue degradation and degeneration; (36) bacterial activities and infections, including lethal factor and other bacterial toxins; (37) viral and other microbial proteases and infections; (38) snake venom and other toxins; (39) industrial manufacturing of extracellular matrix/collagen products; and (40) cosmetics and beauty products, which would include combining MMP inhibitors with collagen and gelatin gel injections to facilitate a youthful and beautiful appearance. These compounds, which can be used for human beings, animals, and other organisms, will also be conjugated to a variety of materials (e.g. fluorescent dyes, radioactive materials, quantum dots, etc.) for uses in applications ranging from drug-targeting to cell, tissue, and whole-body imaging.
Matrix metalloproteinases (MMPs, matrixins) are a family of zinc-endopeptidase enzymes that are believed to participate in numerous processes, some of which include angiogenesis, embryonic development, morphogenesis, tissue resorption and remodeling, reproduction, arthritis, and the growth, progression, invasion, and metastasis of cancerous tumors (Brinckerhoff, C. E., Matrisian, L. M. Matrix metalloproteinases: a tail of a frog that became a prince. Nature Rev. Mol. Cell. Biol. 2002; 3, 207-214; Egeblad, M., Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nature Rev. Cancer 2002; 2, 163-175; Overall, C. M., López-Otín, C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat. Rev. Cancer. 2002; 2, 657-672; Coussens, L. M., Fingleton, B., Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science. 2002; 295, 2387-2392). The contribution of matrix metalloproteinases to these processes is achieved through their digestion of the extracellular matrix (ECM), proteolytic cleavage of cell surface proteins, and the processing of various growth factors, cytokines, and chemokines (Overall, C. M. Molecular determinants of metalloproteinase substrate specificity: matrix metalloproteinase substrate binding domains, modules, and exosites. Molec. Biotech. 2002; 22, 51-86). At least twenty-five MMPs have been reported in humans and other vertebrates. Many MMPs have been reported to play multiple functions in ECM remodeling, development, growth, morphogenesis, and various pathologies. For example, mice deficient for membrane-type 1 matrix metalloproteinase (MT1-MMP) developed dwarfism, osteopenia, arthritis, craniofacial dysmorphism, and soft-tissue fibrosis due to the ablation of a collagenolytic activity that is essential for the modeling of skeletal and extraskeletal connective tissues (Holmbeck, K., Bianco, P., Caterina, J., Yamada, S., Kromer, M., Kuznetsov, S. A., Mankani, M., Robey, P. G., Poole, A. R., Pidoux, I., Ward, J. M., Birkedal-Hansen, H. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell, 1999; 99, 81-92). In contrast to a constructive role for MT1-MMP in embryo development, this MMP is essential for promoting 3-dimensional tumor growth and invasion in vitro and in vivo with aberrant expression suggesting a deleterious role (Hotary, K. B., Allen, E. D., Brooks, P. C., Datta, N. S., Long, M. W., Weiss, S. J. Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell, 2003; 114, 33-45). MT1-MMP may be involved in oncogenesis and energy metabolism in cancer cells (Golubkov, V. S., Chekanov, A. V., Savinov, A. Y., Rozanov, D. V., Golubkova, N. V., Strongin, A. Y. Membrane type-1 matrix metalloproteinase confers aneuploidy and tumorigenicity on mammary epithelial cells. Cancer Res. 2006; 66, 10460-10465; Radichev, I. A., Remacle, A. G., Sounni, N. E., Shiryaev, S. A., Rozanov, D. V., Zhu, W., Golubkova, N. V., Postnova, T. I., Golubkov, V. S., Strongin, A. Y. Biochemical evidence of the interactions of membrane type-1 matrix metalloproteinase (MT1-MMP) with adenine nucleotide translocator (ANT): potential implications linking proteolysis with energy metabolism in cancer cells. Biochem J. 2009; 420, 37-47). MT1-MMP also controls the white adipose tissue formation in vivo and may be a target for obesity treatment (Chun, T. H., Notary, K. B., Sabeh, F., Saltiel, A. R., Allen, E. D., and Weiss, S. J. A pericellular collagenase directs the 3-dimensional development of white adipose tissue. Cell. 2006; 125, 577-591). Increasing evidence has indicated that MMPs, especially MMP-9, are involved in the pathogenesis of asthma, chronic obstructive pulmonary disease, and multiple sclerosis (Demedts, I. K., Brusselle, G. G., Bracke, K. R., Vermaelen, K. Y., Pauwels, R. A. Matrix metalloproteinases in asthma and COPD. Curr. Opin. Pharmacol. 2005; 5, 257-263; M. E. Muroski, M. D. Roycik, R. G. Newcomer, P. E. Van den Steen, G. Opdenakker, H. R. Monroe, Z. J. Sahab, and Q.-X. Sang. Matrix Metalloproteinase-9/Gelatinase B is a Putative Therapeutic Target of Chronic Obstructive Pulmonary Disease and Multiple Sclerosis. Curr. Pharma. Biotechnol., 2008; 9, 34-46). It is reported that many new extracellular protease inhibitors are under clinical investigation and new therapies based on protease inhibition will be in fruition in the future (Cudic, M., Fields, G. B. Extracellular proteases as targets for drug development. Curr. Protein Pept. Sci. 2009; 10, 297-307; M. D. Roycik, X. Fang, and Q.-X. Sang. A fresh prospect of extracellular matrix hydrolytic enzymes and their substrates. Curr. Pharmaceutical Design. 2009; 15, 1295-1308; Morrison C J, Butler G S, Rodriguez D, Overall C M. Matrix metalloproteinase proteomics: substrates, targets, and therapy. Curr. Opin. Cell Biol. 2009 Jul. 16. [Epub ahead of print]). Thus, selective inhibition of certain MMP family members, specifically those modulating certain pathophysiologies and disease conditions, are highly desirable.